Influence of Role Expectancy on Patient-Reported Outcomes Among Patients With Migraine

Key Points Question Does the assigned role an individual accepts (ie, that of a patient vs a healthy control) influence clinical patient-reported outcomes? Findings In this randomized clinical trial of 244 individuals with migraine, those who were randomly assigned to the role as a patient presented with significantly different clinical outcomes compared with patients who were assigned the role of a healthy control. Meaning These results suggest that clinicians may need to be vigilant regarding the effect of expectations and the role of a patient with respect to study outcomes.


ABSTRACT
Background: Migraine is frequently associated with motion sickness, vestibular symptoms, and abnormal motion and visual processing.The triggered clinical symptoms and the brain mechanisms during self-motion visual stimulation were not yet investigated in this population.
Objective: To investigate the behavioral and brain responses from a visually simulated roller coaster ride of patients with migraine and headache-free controls.
Methods: Consecutive patients from a university-based hospital headache clinic (UKE) will be included, if eligible according to inclusion and exclusion criteria.A behavioral study will be conducted in order to assess the responses of 100 patients and 50 headache free controls to a self-motion stimulation paradigm based on a customized roller coaster video.Half of the patients with migraine will be informed that the study aims to investigate vestibular disorders, in order to consider a response bias in the analysis.A blinded examiner will give a questionnaire to the patient regarding features of migraine, vestibular symptoms, and motion sickness.Disability questionnaires related to migraine (MIDAS), dizziness (DHI) and motion sickness (MSSQ) will also be administered.During the video, quiet standing balance will be assessed on a foam surface using a camera and a marker positioned above the participant's head.Antero-posterior and medio-lateral displacement of the center of pressure will be measured.After watching the video, subjects will be asked about triggered symptoms and its duration.
Subsequently, an additional fMRI study will be conducted with 20 patients with migraine and 20 controls in order to verify the brain responses to the paradigm.Blocks of roller coaster stimuli into several directions/velocities versus slow speed into a single direction will be randomly presented during a 30-minute period and displayed by means of Presentation 14.1 inside a Siemens Trio 3T scanner.
Whole brain BOLD fMRI data will be acquired and processed with SPM12 and MATLAB.Groups will be compared for all outcomes with a significance level of 5% and a correlation between imaging and clinical features will also be assessed.

Expected results:
The results of this project will elucidate the behavioral and brain responses of patients with migraine to self-movement simulated stimulus.We expect to find greater intolerance and associated symptoms to the stimulus in this group of patients, as well as a different pattern of brain activation, especially in regions such as the insula, cerebellum and brainstem.This outcome will be subject to context (response bias).

BACKGROUND
Migraine is a chronic neurologic disorder characterized by episodic headache attacks with a worldwide prevalence ranging between 11% to 15%. 1,2 t is ranked as the third most prevalent neurologic disorder and the first cause of years lived with disability in individuals under 50 years of age. 3,4 urther than headache, patients with migraine may present gastrointestinal disorders, several neurologic and autonomic alterations, among many other comorbidities. 5,6 ][9][10][11][12][13][14][15] Motion sickness (nausea) is indeed considered part of the diagnostic criteria for migraine according to the International Classification of Headache Disorders (ICHD-3). 16In addition, dizziness can be considered inherent of the migraine condition, 7,8 along with other common symptoms such as cutaneous allodynia, 17 photo and phonophobia. 18graineurs exhibit functional movement alterations from an early age 19 with a delayed development and integration impairment of the visual motion processing. 20,21 nder visual motion stimuli, this anomaly in the motion/orientation perception [22][23][24][25][26][27] and processing pathways is still observed in adults [25][26][27][28][29][30] and can induce balance instability. 31,32 airment of balance control is a common sign related to motion perception alterations and vestibular symptoms.It was also already verified that patients with migraine exhibit balance control changes in conditions of simple quiet standing 7,[33][34][35][36][37][38][39][40][41][42] and during functional activities such as walking, transposing obstacles or sit to standing tasks. 37,41 n the presence of migraine aura or migraine chronicity, differences compared to healthy controls are more pronounced, especially regarding the self-report of falls 43 and quiet standing balance tasks. 38,39 5][46] For example, in the context of illusory sensation of self-movements when watching a visual motion stimulus, the visual afferences does not match the vestibular or proprioceptive cues, which is predicted based on previous experiences. 47he divergence between expected and perceived sensorial information can be triggered by underling disturbances at a peripheral level, including the proprioceptive, exteroceptive, labyrinthic and visual afferents; and/or in structures of central nervous system, such as the inner ear, brain stem, cerebellum, basal ganglia and cortical hemispheres. 48,49  mechanism of migraine susceptibility to these symptoms is still not well understood. 10,50 sibilities include brain hyperexcitability 15,22,26,29,51,52 and lack of habituation, 26,53 overlap between trigeminal and vestibular pathways, 41,42,[54][55][56] structural and functional abnormality of the visual processing network, 26,57,58 altered function of the inner ear 33,36,42,59,60 and vasospasm-induced ischemia of the labyrinth and brainstem. 61,62 e studies additionally demonstrate that motion intolerance, vestibular symptoms and abnormalities in eye movements can be related to the known impairment of the cerebellar function and its structural changes in migraine patients. 13-15, 31, 63-70Indeed, extensive sensory input from the vestibular, 71 proprioceptive and visual systems converge into the cerebellum 72 and into the brainstem. 73[82][83] Moving dots, black and white checkerboards, rings and gratings, among other types of visual stimuli, have been widely used to stimulate migraine patients, with the aim to study the motion/visual processing and the pathophysiological mechanisms related to this disease.Visual stimulation can activate the nociceptive trigeminal nucleus in chronic migraine 84 and trigger associated symptoms such as nausea, photophobia, tenderness and pain sensitivity. 11Furthermore, trigeminal stimulation can induce vestibular asymmetry in the headache-free interval. 85wever, the brain processing mechanisms through functional magnetic resonance imaging (fMRI) related to the self-motion under gravity conditions have not been investigated in migraineurs so far.Visual self-motion stimuli, based mainly on roller coaster simulated rides, have been used to study the motion and gravity processing, 86 motion sickness, [87][88][89] and brain physiologic mechanisms, [90][91][92][93][94] in both healthy subjects [86][87][88][89][92][93][94] and patients with vestibular disorders. 90 Vertcal motion stimulus can induce activations in the insula, 90,92,94 the parieto-insular vestibular cortex, 93 thalamus, pre-frontal areas and the cerebellum; 94 while horizontal motion activate mainly the hippocampus and parahippocampal regions.94 Taking all these previous described evidence together, we hypothesize that patients with migraine would exhibit differences compared to headache-free subjects regarding clinical symptoms and also brain processing mechanisms during visual self-motion stimulation by means of roller coaster simulation rides.We also suggest that the heterogeneity of migraine presentation considering the presence/absence of vestibular symptoms, presence of aura and/or attacks frequency would influence the behavior and brain responses to the stimuli.

Significance
The clinical symptoms and the brain mechanisms triggered by self-motion stimulation were not yet investigated in patients with migraine.Since those patients exhibit substantial alterations in the cerebellum, impairment of visual, vestibular and motion processing and also self-report of motion sickness susceptibility, balance changes and vestibular symptoms; the study of the mechanisms under gravity simulation is pertinent.The understanding of the brain and cerebellar activity under simulated roller coaster rides would contribute to the knowledge of migraine pathophysiologic mechanisms and interactions with established disease comorbidities.
Furthermore, it would allow the identification of common or distinct brain functioning among patients considering the differences in the migraine spectrum, including attack frequency, presence/absence of aura and self-report of motion sickness or vestibular symptoms.The identification of differences among patients' presentation is of importance due to its potential influence on the assessment, treatment plan, and prognosis.It would improve the recognition of different levels of disability and may make feasible the inclusion of a tailored rationale of treatment in the clinical practice.

OBJECTIVES
This present study aims to investigate the clinical responses and also the brain activity of patients with migraine during visual self-movement stimulation.

METHODS
This cross-sectional study will be conducted at the headache clinic of the University Medical Center Hamburg-Eppendorf, Germany.Patients with migraine will be identified by neurologists with expertise in headaches and diagnosed according to the ICHD-III. 16Two experiments will be performed in order to address the study objectives.
All participants will sign the study consent form before enrollment.Once enrolled, the subjects will have the right to pause or terminate his/her participation at any time during the study.

Behavioral study -Experiment I
In order to test the patients' response to the roller coaster paradigm, initially they will be invited to watch a roller coaster video and clinical measurements will be recorded.

Sample
The study enrollment consists initially of 100 consecutive subjects with migraine and 50 controls.After a pilot phase, a sample size calculation will be performed, and the number of participants will be redefined in order to ensure a power of 80% and at least moderate effect size (>0.5).In order to verify the effect of response bias, part of the patients with migraine will be informed that the study aims to investigate vestibular disorders instead of headache disorders.
Eligible patients according to the inclusion and exclusion criteria (Table 1) will be invited to participate.

Table 1. Enrollment criteria of the experiment I.
Inclusion criteria: 1. Males and females with age over 18,

Written consent to the investigation Exclusion Criteria:
1. Migraine attack on the day of the appointment, 2. History of any neurological disease, 3.No other relevant headache diagnosis other than migraine (e.g., medication overuse headache).4. Self-report of diagnosis of vestibular disease, 5. History of trauma or pathology of the cervical spine (e.g., whiplash associated disorder), 6. Pregnancy, 7. Other relevant musculoskeletal, systemic or psychiatric disease.

A. Roller Coaster Paradigm
A roller coaster ride was simulated by displaying a first-person perspective view of forward self-motion (Fig. 1) in a full HD monitor (23.8",EIZO, California, EUA).The custom roller-coaster used in this study was created using the No Limits Coaster software (www.nolimitscoaster.com,Mad Data, Joerg Henseler, Erkrath, Germany).The ride simulation consists of animated scenes with tracks in the up, down, left and right direction, with horizontal and vertical perspectives.The acceleration and movement velocity varied according to the ride direction.

B. Clinical assessment
An assessor blinded to the patient group allocation will carry out all the assessment procedures.
After the physician consultation, the eligible patients that agreed to participate in the study will receive a set of questionnaires with inquiries regarding demographical and headache features including age, occupation, migraine onset, intensity, frequency and migraine disability (migraine disability assessment questionnaire -MIDAS). 95Furthermore, they will complete the PHQ-8 questionnaire in order to screen for presence of depression.
The presence of vestibular symptoms will also be assessed.Patients will be encouraged to describe their symptoms according to the Barany's Classification of Vestibular Disorders 96 including its form (internal/external vertigo, dizziness or postural symptoms), its duration, frequency and concomitant occurrence with migraine attacks.Motion sickness susceptibility with the MSSQ -short version questionnaire 97 and the disability level related to vestibular symptoms with the Dizziness Handicap Inventory (DHI-G) will be assessed. 98A staff member will be available at all times during the data collection in order to solve any possible query.
After the interview procedure, patients will be exposed to the roller coaster paradigm.They will be asked to stay in a sitting position resting their faces in a chin-head rest and concentrate in the screen positioned 25 cm from the head, in the eye level.The duration of the video is 5 minutes and patients will be asked about triggered symptoms following the video (i.e.motion sickness, dizziness) and its duration will be recorded.

fMRI Study -Experiment II
Once it was verified that the virtual roller coaster stimulation can trigger vestibular symptoms in migraine patients, an fMRI assessment will be carried out in order to understand the brain responses to the visual self-motion stimuli.

Sample
Twenty patients with migraine and twenty controls will be invited to participate in the study according to the following inclusion/exclusion criteria (table 2).

Inclusion criteria: Study Procedures
The same paradigm described above for the behavioral study will be displayed in AVI videos using Presentation 14.1 (Neurobehavioral Systems Inc., Albany, Canada), at 1024×768 pixels, 60 frames per second, 24°×19° visual angle.Blocks of roller coaster stimuli motion (30sec.)will be interleaved with low speed roller coaster motion into a single direction (15sec.duration) for 30 minutes.The order of the roller coaster direction component was randomly changed in each block in order to avoid habituation during fMRI scanning.

A. fMRI acquisition
The image scanning will be performed in a Siemens Trio 3T scanner (Siemens, Erlangen, Germany) with a 32-channel head coil.Whole brain BOLD fMRI data acquisition will use an echo planar imaging sequence (repetition time 2.62 s, echo time 30 ms, flip angle 80 o , field of view 220mm2, acceleration mode GRAPPA, spatial resolution 2.0x2.0x2.0 mm, acquisition matrix 110x110x40), covering the sTN in the brainstem, the cerebellum, the midbrain, insula and most of the cortex.Each volume will consist of 40 axial slices (slice thickness 2 mm, gap 1 mm).

B. Image processing
Functional images will be analyzed using SPM12 and MATLAB (The MathWorks Inc., Natick, MA).During preprocessing, images will be imported and converted to 4D nifti files, denoised via the spatially adaptive nonlocal means algorithm as implemented in the CAT12 toolbox, slice time corrected, realigned, normalized into Montreal Neurological Institute space via a segmentation-normalization sequence, upsampled to a spatial resolution of 1 × 1 × 1 mm3, and smoothed using a 4-mm full width at half maximum isotropic Gaussian kernel.The highpass filters' cutoff frequency will be set to 128 sec.
For each participant, general linear models (GLM) will be used to assess regionally specific effects of stimuli parameters on BOLD activations.Trials will be modeled as epochs of variable duration and convolved with the SPM8 hemodynamic response function.First-level GLMs included motion stimuli in several directions versus slow motion in one direction conditions.

DATA ANALYSIS
Initially, descriptive statistics will be used: absolute and relative frequencies according to the variables characteristics.Continuous variables will be summarized using averages and standard deviations (if normally distributed according to the Kolmogorov-Smirnov or the Shapiro-Wilk test) and median and range if nonparametrically distributed.
Differences between the migraine and control groups will be determined by an independent two-way Student's T-test, or Mann-Whitney U test according to the distribution of the variables for continuous variables balance outcomes, migraine features and demographical data.Categorical variables will be studied using the chi-square or Fisher's exact test.
Differences in brain activity between controls and migraineurs will calculated by independent two-way Student's T-test with an uncorrected threshold of p<0.001.For each contrast of interest, regression coefficients will be calculated between brain activity and clinical features of migraine, DHI-G scores, Midas and MSSQ within the migraine group to test the hypothesis that disease severity modulates brain responses.The significance level will be set at 0.05 and p-value, and 95% confidence intervals will be reported.

Figure 1 .
Figure 1.Example of patients' screen view of the roller coaster paradigm.It is simulated as if the viewer were a passenger sitting in the front-car and looking straight ahead.